Interview with Dr. Jonathan Choy

Associate Professor, Department of Molecular Biology & Biochemistry

Dr. Choy’s research program is driven by his overriding interest in understanding how the human body’s inflammatory and immune responses develop inappropriately to cause organ transplant rejection and some rheumatological diseases. His research group is committed to making discoveries that will make people healthier. They aim to understand the mechanisms and effectiveness of certain treatments, with an ultimate goal of developing or informing strategies for tackling a range of health conditions.

What life experiences led you to pursue a career in research?
As an undergraduate at Simon Fraser University, my engagement in research through the Science Co-operative Education (Co-op) program had a large impact on me. I had great mentors who were passionate about research and discovery, and they gave me autonomy in my projects. Through research experiences in academic laboratories and pharmaceutical companies I became passionate about making discoveries that have a positive impact on human health.

What is the motivation behind your research program?
Organ transplants save lives but eventually almost all transplants will fail because the immune system of the recipient rejects the grafted tissue. There are also diseases – called autoimmune diseases – in which the immune system inappropriately mounts a response against the individual’s own cells. If we could understand the components of the immune response that cause the rejection and initiate the response to an individual’s own cells, then we could potentially target these components specifically to prevent rejection and autoimmune diseases.

What is the main challenge in treating immunological diseases?
The most challenging aspect is finding specific immunological processes that can be affected in a way that controls the undesirable part of the immune response (i.e., rejection or tissue injury), maintains the immune response to pathogens, and does not cause undesirable side effects. This is not easy because the immune system has evolved to protect against infections, yet the same processes also cause rejection and autoimmune diseases.

What is your most recent discovery and its significance?
Recently, we examined the role of a protein called IL-6, which is induced very early after transplantation, in the development of rejection. Biological agents that block IL-6 are already clinically available for the treatment of some autoimmune diseases. We discovered that IL-6 production from the graft supports the expansion of T cells—key cells of the immune system that cause the rejection response—by increasing their proliferation and survival. Ultimately, our findings could help scientists develop better ways to target IL-6 activity to reduce transplant rejection.

How do you envision targeting IL-6 to reduce transplant rejection?
IL-6 can be targeted by using a neutralizing antibody to the IL-6 receptor or by small molecules that inhibit the signalling pathways that it activates in cells. The antibody method is a more specific approach because small molecules can affect other signalling pathways. Methods using neutralizing antibodies for the receptor are available to treat rheumatoid arthritis and other autoimmune diseases.

The challenge is to go beyond inhibiting IL-6 everywhere to specifically inhibiting the IL-6 response that causes organ transplant rejection. That necessitates understanding how IL-6 signals within tissues and immune cells and dissociating those signalling processes so they can be targeted separately.

Will it be possible to target the IL-6 activity that causes transplant rejection while not damaging its positive roles?
It depends on the mechanisms involved and where the IL-6 receptor is located. There is evidence that some inflammatory conditions are mediated mostly by one type of signalling mechanism and tissue repair responses by another. It will be difficult to dissociate these roles, but there is potential to do so.

What is the funding landscape like for your particular program?
I started at a fortunate time, when the funding opportunities were decent; it's more difficult now for early career investigators. In general, funding for biomedical research is hard to get. Success rates are at historically low levels and there has been re-structuring of key funding programs. Researchers are concerned that if this low level of funding persists, it will have a long-lasting impact on the ability of Canadian scientists to make contributions that benefit the health of Canadians.

Currently, I am funded mainly by the Natural Sciences and Engineering Council of Canada (NSERC) and the Heart and Stroke Foundation of Canada. We also have shorter-term funding from other agencies. For example, I receive support from the Canadian Glycomics Network (GlycoNet), which is supported through the Networks of Centres of Excellence of Canada program.

What is the goal ofyour GlycoNet-funded research project?
We received GlycoNet funding to explore the idea that transplant rejection might be affected by a specific protein modification, called O-GlcNAcylation, in which proteins have a certain type of sugar molecule connected to them. Studies show that O-GlcNAcylation affects cellular processes that could affect the immune response in transplant rejection. We are investigating whether this sugar modification affects organ transplant rejection in experimental models and, if it does, how this occurs and how it can be targeted therapeutically.

What are your thoughts on the research network approach to funding research?
I think the large network funding approach is valuable. It provides directed support for important strategic areas, which is critical for bringing teams together to maximize efforts toward focused research goals. It also leverages funds from partnerships, which can increase overall funding.

The challenge is implementing these programs in a way that ensures that the funds are used efficiently, yet are flexible enough to support discovery. Care must be taken to ensure that this funding model does not replace that of investigator-initiated research programs, which are available to everyone. Reducing support for investigator-led research grants erodes the foundation of expertise that is needed to support strategically directed initiatives in the future.

What does your participation in GlycoNet bring to your trainees?
Participation in GlycoNet provides a fantastic environment for trainees in my lab. The Network provides training opportunities that are useful for career development in the current research landscape. It also provides training in transferrable skills, such as project management and patent development. In addition, the Network provides visibility for our work and the associated trainees, which is great for developing a professional network.

What do you think the next big thing will be in your field of research?
It will be identifying immune modulatory approaches that can specifically activate or inactivate a response in immune conditions and diseases. The Holy Grail is the induction of tolerance, in which the immune system is inactivated to a specific target but the responses to all other targets are maintained. Finding how to induce tolerance safely in individuals would allow for the complete success of organ transplantation and the cure of autoimmune diseases.

This is complicated by the huge individual variation in the human immune response. The causes of immunological conditions involve an unfortunate combination of events for the individual, and individual variability in the immune response and environmental experiences complicates the development of treatments. However, there are examples that this can be done, such as the recent progress in preventing peanut allergies by encouraging exposure at an early age. Future advances in developing immune modulatory approaches are likely to have a large impact on human health.